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Gale Encyclopedia of Genetic Disorder / Gale Encyclopedia of Genetic Disorders, Two Volume Set - Volume 2 - M-Z - I

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Osteoporosis

I Osteoporosis

Definition

Osteoporosis is a disease characterized by low bone mass and deterioration of bone tissues, leading to bone fragility and, consequently, an increase in fracture risk.

Description

The term osteoporosis comes from the Greek word osteon, meaning bone, and porus, meaning pore or passage. Osteoporosis literally makes bones porous. The amount of calcium stored in bones decreases over time causing the skeleton to weaken.

In the body of early adults, both the mineral portion and the framework of bone is in constant flux. Old tissue is broken down and reabsorbed and new bone is created at approximately the same rate. In later years, this rate of renewal begins to slow behind the rate of removal. This slowing is what leaves the bones thinner and more fragile. The most typical sites of fractures related to osteoporosis are the hip, spine, wrist, and ribs, although the disease can affect any bone in the body.

The average woman acquires 98% of her skeletal mass by approximately age 20. Building strong bones during childhood and adolescence is a key defense against developing osteoporosis later. There are four main steps to preventing osteoporosis: consuming a balanced diet rich in calcium and vitamin D; participating in weightbearing exercise; following a healthy lifestyle, including no smoking and limited alcohol intake; and testing bone density and taking medication when appropriate.

Type I, postmenopausal osteoporosis, is the most common. It is usually a consequence of reproductive hormone deficiency, and afflicts mostly women over age 50. The disorder typically appears within the first ten or twenty years after menopause. Men may also develop the disorder, usually around 50-60 years of age, as a result of:

Prolonged exposure to certain medications such as steroids used to treat asthma or arthritis, anticonvulsants, aluminum-containing antacids, and certain cancer treatments

Chronic disease that affects the kidneys, lungs, stomach, and intestines and alters hormone levels

Undiagnosed low levels of the sex hormone testosterone

Lifestyle habits such as smoking, excessive alcohol use, low calcium intake, inadequate physical exercise

Type II, senile osteoporosis, affects both men and women over the age of 70, although women are twice as likely to develop the disorder.

In some cases, osteoporosis is secondary to another cause. It can accompany endocrine disorders such as acromegaly and Cushing syndrome. It results from excessive use of drugs such as corticosteroids. In these cases, the treatment is directed at curing the principal ailment or at not using the offending drug. Blood or urine tests will diagnose other causes of bone loss or bone density.

Genetic profile

Osteoporosis results from a complex interaction between genetic and environmental factors throughout life. Evidence suggests that peak bone mass is inherited, but current genetic markers are only able to explain a small proportion of the variation in individual bone mass or fracture risk. At this time, no specific mode of inheritance has been identified. Heritability of bone mass has been estimated to account for 60-90% of its variance. Studies have shown reduced bone mass in daughters of osteoporotic women when compared with controls; in men and women who have first-degree relatives with osteoporosis; and in perimenopausal women who have a family history of hip fracture. Body weight in infancy may be a determinant of adult bone mineral area.

Some scientists think that environmental influences during early life interact with the genome to establish the functional level of a variety of metabolic processes involved in skeletal growth.

Many candidate genes exist for osteoporosis, however relatively few have been studied. The first candidate gene to be identified was the vitamin D receptor (VDR) gene, and studies are ongoing as to how much this gene accounts for variance in bone mass. The response of bone mass to dietary supplementation with vitamin D and calcium is known to be dependent, in part, on VDR polymorphisms. Other genes may aid in establishing who would benefit from treatments like hormone replacement therapy, bisphosophonates, or exercise. Associations between bone mass and polymorphisms have also been found in the estrogen receptor gene, the interleukin-6 genes, the transforming growth factor beta, and a binding site of the collagen type I alpha1 (COLIA1) gene.

The risk of osteoporosis is greatly determined by peak bone mass, and any gene linked to fractures in the elderly may possibly be associated with low bone mass in children as well.

Environmental influences such as diet, climate, and physical exercise may have significant impact on gene expression, as well. In particular, malnutrition early in life is likely to have permanent effects resulting in lowered bone mass.

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Demographics

Significant risk has been reported in people of all ethnic backgrounds. Asian and white women are at greatest risk of bone thinning because they generally have the lowest bone density. Although the risk is smaller, African-American and Hispanic-American women should take percaution, as well. An estimated 10% of African-American women over age 50 have osteoporosis and an additional 30% have low bone density that puts them at risk of developing osteoporosis.

Women in general have a four times greater risk than men of developing osteoporosis, and 80% of those affected by osteoporosis are women. In the United States, an estimated eight million American women and two million men have osteoporosis.

An osteoporosis-related fracture will occur in one in two women and one in eight men over the age of 50.

Signs and symptoms

Often called “the silent disease” because bone loss occurs without symptoms, people may not know that they have osteoporosis until they have a fracture from a minor bump or fall, or a vertebra collapses. Physical signs of osteoporosis include back pain, loss of height over time, stooped posture, and fractures of vertebrae, wrists, or hips. Osteoporosis can be detected by a bone mineral density test or even a regular x ray.

Without preventive treatment, women can lose up to 20% of their bone mass in the first five to seven years following menopause, making them more susceptible to osteoporosis.

Over many years, a sequence of spinal compression fractures may cause kyphosis, the bent-over posture known as dowager’s or widow’s hump. These fractures rarely require surgery, and they can range from causing minor discomfort to severe painful episodes of backache. In either case, pain generally subsides gradually over one to two months.

Diagnosis

Since osteoporosis can develop undetected for decades until a fracture occurs, early diagnosis is important.

A bone mineral density test (BMD) is the only way to diagnose osteoporosis and determine risk for future fracture. The painless, noninvasive test measures bone density and helps determine whether medication is needed to help maintain bone mass, prevent further bone loss, and reduce fracture risk.

K E Y T E R M S

Corticosteroids—Anti-inflammatory medications. Related to cortisol, a naturally produced hormone that controls many body functions.

Menopause—Cessation of menstruation in the human female, usually occurring between the ages of 46 and 50.

Osteopenic—Bone density that is somewhat low, but not osteoporotic.

Polymorphism—A change in the base pair sequence of DNA that may or may not be associated with a disease.

Several different machines measure bone density. Central machines, such as the dual energy x-ray absorptiometry (DXA or DEXA) and quantitative computed tomography (QCT), measure density in the hip, spine and total body. Peripheral machines, such as radiographic absorptiometry (RA), peripheral dual energy x-ray absorptiometry (pDXA), and peripheral quantitative computed tomography (pQCT), measure density in the finger, wrist, kneecap, shin bone, and heel.

A physician may be able to observe osteoporotic bone in a routine spinal x ray, however, BMD tests are more accurate and can measure small percentages of lost bone density. In an x ray, osteoporotic bone appears less dense and the image is less distinct, suggesting weaker bone.

There are no official guidelines for osteoporosis screening. Some physicians recommend bone density testing at menopause to begin preventive treatment if necessary. Generally, testing is recommended for postmenopausal women who have suffered a bone fracture after menopause or who have gone through menopause and have at least one risk factor for the disease. The major risk factors are low body weight, low calcium intake, poor health, and a history of osteoporosis in the family. The test is usually recommended for all women over 65.

Testing may also be recommended for elderly men with one of the following risk factors: bone fracture, poor health, or low testosterone levels.

Treatment and management

There a number of options for preventing and treating bone loss.

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Bone atrophy due to osteoporosis in a human femur. The ball joint has become porous and brittle. (Custom Medical Stock Photo, Inc.)

Therapeutic options

Various therapies have been shown to be effective in preventing bone loss and increasing bone mass. These include:

Estrogen. For women with postmenopausal osteoporosis, estrogen replacement therapy helps halt bone loss and exerts a modest bone-building effect. Stopping estrogen therapy restarts bone loss, so long-term treatment is usually recommended. For women entering menopause, some physicians recommend estrogen replacement therapy to replace the decreasing supply of naturally-occurring estrogen in the body and enable the skeleton to slow its rate of absorption and retain calcium. Estrogen is considered the best treatment against osteoporosis. Physicians may recommend combination estrogen and progesterone replacement therapy in women who have an intact uterus in order to reduce endometrial cancer risk. Some studies indicate a relationship between estrogen use and breast cancer while

other studies indicate no relationship at all; the issue is still to be determined.

Raloxifene. One of a class of drugs called selective estrogen receptor modulators (SERMs) that appear to prevent bone loss, raloxifene (Evista) produces small increases in bone mass. It is approved for the prevention and treatment of osteoporosis. Like estrogens, SERMs produce changes in blood lipids that may protect against heart disease, although the effects are not as potent as that of estrogen. Unlike estrogens, SERMs do not appear to stimulate uterine or breast tissue.

Alendronate. One of a class of medications called bisphosphonates, alendronate (Fosamax) may prevent bone loss, increase bone mass, and reduce the risk of fractures.

Risedronate. Also from the bisphosphonate family, risedronate (Actonel) has been shown to reduce bone loss, increase bone density, and reduce the risk of fractures.

Calcitonin. A hormone that regulates calcium levels in the blood, calcitonin and may prevent bone loss. It is approved for treatment of diagnosed osteoporosis.

Preventive options

Measures have been identified that improve bone strength over the life span. Physicians recommend that all adult men and women, but particularly men and women over the age of 50, take the following measures to prevent osteoporosis:

Consume at least 1,000 mg calcium. Foods high in calcium include dairy products, leafy green vegetables, beans, nuts and whole-grain cereals. Supplements may be taken if adequate intake cannot be achieved through diet.

Consume 400 IU of vitamin D to enhance calcium absorption.

Participate in regular weight-bearing exercise, such as walking, jogging, tennis, weight-lifting, and crosscounty skiing, to strengthen bones.

Stop smoking.

Reduce intake of caffeine to not more than three cups a day.

Limit alcohol to not more than two drinks per day.

Avoid excessive amounts of dietary fiber as it binds to calcium and may interfere with absorption.

Making the house a safer place against falls can decrease risk of fracture in people with osteoporosis. Install handrails on the stairs; remove loose throw rugs; keep rooms and hallways well-lit including night lights; install handrails beside the tub, shower and toilet; place

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nonskid mats in the bathtub, shower, and on tile bathroom floors.

If fractures occur, treatment may require casts, braces, physical therapy and surgery to assist bone healing.

Prognosis

When osteoporosis is untreated, it can cause serious disability. Osteoperosis can be managed with proper medical and self-care.

Osteoporosis is associated with 40,000 deaths annually, mostly from complications of surgery or immobilization after hip fractures.

Resources

BOOKS

Osteoporosis in Men: The effects of gender on skeletal health, edited by Eric S. Orwoll. Academic Press, 1999.

Osteoporosis: Diagnosis and management, edited by Pierre J. Meunier. Mosby, 1998.

PERIODICALS

Altkorn, Diane, Tamara Vokes, and Alice T. D. Hughes. “Treatment of Postmenopausal Osteoporosis.” JAMA: Journal of the American Medical Association 11 (2001): 1415 .

NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. “Osteoporosis Prevention, Diagnosis, and Therapy.” JAMA: Journal of the American Medical Association 285 (2001): 785 .

ORGANIZATIONS

Foundation for Osteoporosis Research and Education. 300 27th St., Oakland, CA 94612. (888) 266-3015. http://www

.fore.org .

WEBSITES

National Osteoporosis Foundation. http://www.nof.org . Osteoporosis and Related Bone Diseases–National Resource

Center. National Institutes of Health. http://www.osteo

.org .

Jennifer F. Wilson, MS

I Otopalatodigital syndrome

Definition

Otopalatodigital (OPD) syndrome, also called digitootopalatal syndrome or palatootodigital syndrome, is a rare X-linked genetic disorder that affects bone and facial structure. OPD is fully expressed in males. Females are only mildly affected.

Description

There are two forms of OPD syndrome. Type I is inherited through an X-linked trait with intermediate expression in females while type II is inherited through an X-linked recesssive trait. OPD syndrome type I is also called Taybi syndrome. OPD syndrome type II is alternately called Andre syndrome, cranioorodigital syndrome, or faciopalatoosseous (FPO) syndrome.

A genetic disorder called frontometaphyseal dysplasia, or FMD, has very similar features to type I OPD syndrome.

There are three recognized forms of a genetic disorder called Larsen syndrome: an autosomal dominant type, a recessive type, and a lethal type. All three of these syndromes have similar symptoms to those seen in individuals affected with OPD syndrome. Recent evidence also suggests that Larsen syndrome, recessive type, may in fact be type II OPD syndrome.

As the various names of OPD syndrome suggest, this disorder is characterized by malformations and/or dysfunctions of the ears (-oto-), palate (-palato-), fingers and toes (-digito-), skull (-cranio-), mouth (-oro-), face (- facio-), and bones (-osseo-). Some of the characteristics common to both types of OPD syndrome include: a cleft palate, a prominent forehead, a broad nose, widely spaced eyes (hypertelorism), a downward slanting of the opening between the upper and lower eyelids (palpebral fissures), conductive hearing loss, short fingers and toes (brachydactyly), an abnormal inward curving of the fingers (clinodactyly), a caved in chest at birth (pectus excavatum); short stature (dwarfism), and a congenital dislocation of the elbows caused by a misalignment of the head of the large bone in the forearm (radius).

Genetic profile

Both forms of OPD syndrome are X-linked. The gene mutation responsible for the appearance of type I OPD syndrome has been tentatively assigned to the Xq28 band. It is also believed that type II OPD syndrome is an allelic variant of type I OPD, which is to say that each form of OPD syndrome is caused by different mutations in the same gene or in overlapping genes at the same chromosomal location. Recessive type Larsen syndrome is also believed to be either another allelic variant of OPD syndrome, or identical to type II OPD syndrome. Another extremely rare genetic disorder, Melnick-Needles syndrome also has an overlapping of symptoms with type II OPD syndrome. It is felt that this syndrome is also possibly an allelic variant of OPD syndrome.

OPD syndrome is transmitted via the X chromosome. A female generally possesses two X chromosomes,

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K E Y T E R M S

Brachydactyly—Abnormal shortness of the fingers and toes.

Cleft palate—A congenital malformation in which there is an abnormal opening in the roof of the mouth that allows the nasal passages and the mouth to be improperly connected.

Clinodactyly—An abnormal inward curving of the fingers or toes.

Conductive hearing loss—Hearing loss that is the result of a dysfunction of the parts of the ear responsible for collecting sound. In this type of hearing loss, the auditory nerve is generally not damaged.

Hypertelorism—A wider-than-normal space between the eyes.

Hypospadias—An abnormality of the penis in which the urethral opening is located on the underside of the penis rather than at its tip.

Omphalocele—A birth defect where the bowel and sometimes the liver, protrudes through an opening in the baby’s abdomen near the umbilical cord.

Palpebral fissures—The opening between the upper and lower eyelids.

Pectus excavatum—An abnormality of the chest in which the sternum (breastbone) sinks inward; sometimes called “funnel chest.”

one from her mother and one from her father. A male generally possesses only a single X chromosome, that from his mother. He gets a Y chromosome from his father. Certain rare exceptions to these inheritance patterns are seen, but in general, a female is an XX and a male is an XY. It is for this reason that X-linked disorders are generally seen in greater numbers of males than females. The male does not possess a second X chromosome that can be expressed. A male either has a mutation on his X chromosome, or he does not. A female, on the other hand, can be either homozygous or heterozygous for an X-linked trait. That is, she can either have two identical copies of this trait (homozygous) or only one copy is this trait (heterozygous).

Type I OPD syndrome is transmitted through a dominant trait. A child of a type I OPD syndrome affected parent has a 50% chance of also being affected with type I OPD syndrome.

Type II OPD syndrome is transmitted through an X- linked recessive trait. A child of a type II OPD syndrome affected parent has a 50% chance of also inheriting the gene for the type II OPD syndrome. Subsequently, if that child is male, he will have expression of the disorder. If it is a female child, then she generally will have milder features. Girls who are homozygous for type II OPD syndrome (inheriting the gene from each parent) will exhibit more severe symptoms than girls who are heterozygous for type II OPD syndrome. Males affected with type II OPD syndrome exhibit symptoms similar to those seen in homozygous girls.

Demographics

As of early 2001, the incidence of occurrence of both forms of OPD syndrome has not been determined. The lack of occurrence rate data is partially due to the fact that type I OPD syndrome can often have only very mild clinical and radiological symptoms, such that it is often not diagnosed, or even noticed, until type I OPD syndrome is recognized in a more severely affected member of the family.

Type I OPD syndrome is more common than type II OPD syndrome, and as of early 2001, nearly 300 cases had been reported in the medical literature. In 1996, only 25 detailed cases of type II OPD syndrome had been described in the medical literature.

Signs and symptoms

The severity of symptoms experienced by those people affected with OPD syndrome varies widely from practically asymptomatic to symptoms so severe that they cause infantile or prenatal death. In type II OPD syndrome, males are generally affected with far more severe symptoms than females.

There are six abnormalities of the face and head that characterize OPD syndrome: a cleft palate, downwardly slanting openings between the eyelids, widely spaced eyes (hypertelorism), a prominent forehead, a broad nose, and conductive hearing loss.

Conductive hearing loss results from a blockage of the auditory canal or some other dysfunction of the eardrum or one of the three small bones within the ear (the stapes, the malleus, and the incus) that are responsible for collecting sound. In this type of hearing loss, the auditory nerve is normal. In individuals affected with OPD syndrome, complete deafness from birth is often observed. In those individuals with partial hearing, speech disabilities related to this hearing loss are quite common.

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In addition to the abnormalities of the head, universal characteristics of OPD syndrome affected individuals also include: abnormally short fingers and toes (brachydactyly); abnormal inward curving of some fingers (clinodactyly); short nails; a congenital dislocation of the elbows, and sometimes the knees; a caved in chest (pectus excavatum) at birth; and, growth retardation.

Symptoms that are characteristic of type I OPD syndrome include: curvature of the spine (scoliosis); generalized bone malformation, particularly in the bones of the limbs and ribcage; broad distal digits, malformed or missing teeth (hypodontia); and, mild mental retardation.

Symptoms that are characteristic of type II OPD syndrome include: low-set ears, flattened vertebrae in the spine, bowing of the bones of the limbs, flexed overlapping digits, a malformation or complete absence of the large bone in the shin (fibula), malformations of the hips, a small opening in the abdominal wall (hernia) at the navel (omphalocele), and a malformation of the male genitalia in which the opening of the urethra is located on the underside of the penis, rather than at the tip of the penis (hypospadias).

Diagnosis

A diagnosis of OPD syndrome is suggested when a patient presents the five characteristic abnormalities of the head and face accompanied by conductive hearing loss. This diagnosis is confirmed by the observance of brachdactyly and congenital dislocation of the elbows and/or knees.

Type I OPD syndrome is differentially diagnosed from type II OPD syndrome by the appearance of scoliosis. Type II OPD syndrome is differentially diagnosed from type I OPD by the presence of an omphalocele and greater malformations of the bones of the ribcage.

Treatment and management

There are currently no treatments aimed specifically at OPD syndrome. Instead, treatment is on a case-by-case and symptom-by-symptom basis.

Malformations of the head and face can generally be corrected, if necessary, by surgeries. In certain instances, the conductive hearing loss experienced by individuals with OPD syndrome may also be corrected through surgery. When it cannot, hearing aids may be required.

Many of the skeletal abnormalities seen in OPD syndrome affected individuals can either be corrected by surgery or can be alleviated through the use of braces until the bones become more fully developed.

Malformations of the male genitalia and the omphalocele observed in type II OPD syndrome affected infants can also be corrected by surgery.

Cleft palate results in an opening of the roof of the mouth. This facial abnormality is one of several characteristics that define otopalatodigital syndrome. (Photo Researchers, Inc.)

Certain OPD affected individuals may also benefit from treatments with growth hormone.

In cases of mild mental retardation or speech problems, early intervention programs for these types of developmental delays may also be of benefit.

Prognosis

Most individuals affected with type I OPD syndrome can expect to lead full lives if medical treatments, including corrective surgeries, are sought. Many individuals affected with type II OPD syndrome die either prior to birth or as infants due to respiratory failure associated with the malformation of the bones of the ribcage. If these individuals survive infancy, they also may expect to live full lives after corrective surgeries and other medical treatments.

Resources

PERIODICALS

Alembik, Y., C. Stoll, and J. Messer. “On the phenotypic overlap between severe oto-palato digital type II syndrome and Larsen syndrome. Variable manifestations of a single autosomal dominant gene.” Genetic Counseling (1997): 133-7.

ORGANIZATIONS

Children’s Craniofacial Association. PO Box 280297, Dallas, TX 75243-4522. (972) 994-9902 or (800) 535-3643. contactcca@ccakids.com. http://www.ccakids.com .

FACES: The National Craniofacial Association. PO Box 11082, Chattanooga, TN 37401. (423) 266-1632 or (800) 332-2373. faces@faces-cranio.org. http://www.faces-cranio.org/ .

Let’s Face It (USA) PO Box 29972, Bellingham, WA 982281972. (360) 676-7325. letsfaceit@faceit.org. http://www

.faceit.org/letsfaceit .

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National Foundation for Facial Reconstruction. 317 East 34th St. #901, New York, NY 10016. (800) 422-3223.http://www.nffr.org .

WEBSITES

“Entry 304120 Cranioorodigital syndrome.” OMIM—Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih

.gov/htbin-post/Omim/dispmim?304120 .

“Entry 311300: Otopalatodigital syndrome.” OMIM—Online

Mendelian Inheritance in Man. http://www.ncbi.nlm.nih

.gov/htbin-post/Omim/dispmim?311300 . “Otopalatodigital (OPD) syndrome I.” Jablonski’s Multiple

Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database. http://www.nlm.nih.gov/cgi/ jablonski/syndrome_cgi?index=517 . (February 27, 2001).

“Otopalatodigital (OPD) syndrome II.” Jablonski’s Multiple

Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database. http://www.nlm.nih.gov/cgi/ jablonski/syndrome_cgi?index=518 . (February 27, 2001).

“Oto Palato Digital Syndrome Type I and II.” NORD—National

Organization for Rare Disorders. http://www

.rarediseases.org .

Paul A. Johnson

I Ovarian cancer

Definition

Ovarian cancer is a disease in which the cells in the ovaries become abnormal and start to grow uncontrollably, forming tumors. Ninety percent of all ovarian cancers develop in the cells that line the surface of the ovaries and are called “epithelial cell tumors.”

Description

The ovaries are a pair of almond-shaped organs that lie in the pelvis on either side of the uterus. The fallopian tubes connect the ovaries to the uterus. The ovaries produce and release an egg each month during a woman’s menstrual cycle. In addition, they also produce the female hormones estrogen and progesterone, which regulate and maintain the proper growth and development of female sexual characteristics.

Ovarian cancer is the fifth most common cancer among women in the United States. It accounts for 4% of all cancers in women. However, ovarian cancer is very difficult to discover in the early stages. This is often because there are no obvious warning signs, and the disease can grow relatively quickly. In addition, the ovaries are situated deep in the abdomen and small tumors may

not be detected easily during a routine physical examination. Because of this, the death rate due to ovarian cancer is higher than that of any other cancer among women, since it may only be detected at advanced stages.

Ovarian cancer can develop at any age, but more than half the diagnoses are among women who are 60 years or older. The vast majority of people with ovarian cancer have no family history of the disease. However, for about 5-10% of individuals, there may be a very strong family history of ovarian cancer or other cancers, such as breast cancer. In these cases, a specific genetic alteration may be in the family, causing a predisposition to ovarian cancer and other associated cancers.

Genetic profile

Cells in ovarian tissue normally divide and grow, according to controls and instructions by various genes. If these genes have changes within them, the instructions for cellular growth and division may go awry. Abnormal, uncontrolled cell growth may occur, causing ovarian cancer. Therefore, all ovarian cancers are genetic because they all result from changes within genes. The difference is that most ovarian cancers are caused by sporadic changes within the genes, and only a minority are caused by inherited genetic alterations. Most ovarian cancers occur later in life after years of exposure to various environmental factors (such as the body’s own hormones, asbestos exposure, or smoking) that can cause sporadic genetic alterations.

A small proportion of ovarian cancer is caused by inherited genetic alterations. As of 2001, a genetic alteration causing a predisposition solely to ovarian cancer has not yet been identified. However, in 1994 a breast and ovarian cancer susceptibility gene, known as BRCA1 (location 17q21), was identified. The discovery of BRCA2 (location 13q12) followed shortly in 1995. Women with alterations in these genes have an increased risk for breast and ovarian cancer, and men have an increased risk for prostate cancer. Men with a BRCA2 alteration have an increased risk for breast cancer. Slightly increased risks for colon and pancreatic cancers (in men and women) are also associated with BRCA2 alterations.

BRCA1 and BRCA2 alterations are inherited in an autosomal dominant manner; an individual who has one copy of a BRCA alteration has a 50% chance to pass it on to each of his or her children, regardless of that child’s gender. Nearly all individuals with BRCA alterations have a family history of the alteration, usually a parent with it. In turn, they also may have a very strong family history of breast, ovarian, prostate, colon, and/or pancreatic cancers. Aside from BRCA1 and BRCA2, there

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likely are other cancer susceptibility genes that are still unknown.

In addition to BRCA1 and BRCA2, ovarian cancer may be present in rare genetic cancer syndromes. In these instances, an individual may have other health problems (unrelated to cancer) and a family history of a wide variety of cancers and symptoms. As an example, Hereditary Non-Polyposis Colorectal Cancer (HNPCC) is a syndrome that often involves cancers of the colon, uterus, ovaries, and stomach. HNPCC is due to changes in several genes including hMLH1, hMSH2, hMSH6, and hPMS2. These genes are unrelated to BRCA1 and BRCA2.

Demographics

On average, a North American woman faces a lifetime risk of approximately 2% to develop ovarian cancer. The incidence of ovarian cancer is higher among Caucasian women. The American Cancer Society states that in the year 2000 about 23,100 new cases of ovarian cancer will be diagnosed in the United States, and 14,000 women will die from the disease. Specific BRCA alterations are common in certain ethnic groups, which may make hereditary ovarian cancer more common in these populations. As of 2001, certain BRCA alterations are more common in the Ashkenazi (Eastern European) Jewish, Icelander, Dutch, French Canadian, and West African populations.

Signs and symptoms

Ovarian cancer has no specific signs or symptoms in the early stages of the disease. However, one may experience some of the following:

Pain or swelling in the abdominal area

Bloating and general feeling of abdominal discomfort

Constipation, nausea, or vomiting

Loss of appetite, tiredness

Unexplained weight gain (generally due to fluid building up from the cancer in the abdomen)

Vaginal bleeding in women who have already gone through menopause

Only a physician can assess whether or not the symptoms are an indication of early ovarian cancer. This is why it is important for a physician to be informed right away if any of the above symptoms are present.

A family history of ovarian cancer puts a woman at an increased risk for developing the disease. In addition, if a woman has had, or has a family history of breast cancer she may be at an increased risk for ovarian cancer. Signs of a possible BRCA1 or BRCA2 alteration in a

K E Y T E R M S

Alteration—Change or mutation in a gene, specifically in the DNA that codes for the gene.

Biopsy—The surgical removal and microscopic examination of living tissue for diagnostic purposes.

Computed tomography (CT) scan—An imaging procedure that produces a three-dimensional picture of organs or structures inside the body, such as the brain.

Laparoscopy—A diagnostic procedure in which a small incision is made in the abdomen and a slender, hollow, lighted instrument is passed through it. The doctor can view the ovaries more closely through the laparoscope, and if necessary, obtain tissue samples for biopsy.

Laparotomy—An operation in which the abdominal cavity is opened up.

Magnetic resonance imaging (MRI)—A technique that employs magnetic fields and radio waves to create detailed images of internal body structures and organs, including the brain.

Pelvic examination—Physical examination performed by a physician, often associated with a Pap smear. The physician inserts his/her finger into a woman’s vagina, attempting to feel the ovaries directly.

Transvaginal ultrasound—A way to view the ovaries using sound waves. A probe is inserted into the vagina and the ovaries can be seen. Color doppler imaging measures the amount of blood flow, as tumors sometimes have high levels of blood flow.

family, signifying hereditary breast or ovarian cancer, include:

Several relatives with cancer

A large number of relatives with cancer versus unaffected relatives

Close genetic relationships between people with cancer, such as parent-child, sibling-sibling

Earlier ages of cancer onset, such as before ages 45-50

An individual with both breast and ovarian cancer

An individual with bilateral or multi-focal breast cancer

The presence of ovarian, prostate, colon, or pancreatic cancers in the same family

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• Case(s) of breast cancer in men

Suspicion of a BRCA alteration may be raised if someone has the above features in their family and they are of a particular ethnic group, such as Ashkenazi Jewish. This is because specific BRCA1 and BRCA2 alterations are known to be more common in this group of individuals.

Diagnosis

If a woman has symptoms of ovarian cancer, a pelvic examination is usually conducted to feel the ovaries to see if they have enlarged, indicative of a tumor. Blood tests to determine the level of a protein, known as carbohydrate antigen 125 (CA-125), may be done. CA-125 blood levels can be high when a woman has ovarian cancer. Additionally, a pelvic or transvaginal ultrasound (with color Doppler imaging) may be used to get several views of the ovaries, carefully checking their shape and structure. A CT scan may be helpful if the ultrasound is technically unsatisfactory for accurate interpretation.

A biopsy and surgery is necessary in order to determine the type of tumor, as not all tumors are cancerous. If the tumor appears to be small, a procedure known as laparoscopy may be used. A tiny incision is made in the abdomen and a slender, hollow, lighted instrument is inserted through it. This enables the doctor to view the ovary more closely and to obtain a biopsy. If the ovary has suspicious findings on laparoscopy and biopsy, a laparotomy (open surgery performed under general anesthesia) and removal of that ovary is usually performed. Large masses are investigated by open surgery.

Standard imaging techniques such as Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) may be used to determine if the disease has metastasized (spread) to other parts of the body.

As of 2001, there is DNA-based genetic testing to identify a BRCA1 or BRCA2 alteration in an individual. In the United States, Myriad Laboratories in Utah is the only place to offer this costly testing (as of 2001, it is about $2,700 for initial analysis). A blood sample is used, and both BRCA genes are studied for alterations. There is also targeted testing for people in high-risk ethnic groups (such as Ashkenazi Jewish) in which only the common BRCA alterations can be tested. Even with current technology (as of 2001), only certain regions of the BRCA genes can be studied, which leaves some alterations unable to be found.

For women without cancer who test positive for a BRCA alteration, this now places them at a significantly increased risk to develop the associated cancers. A woman’s risks associated with a BRCA1 alteration are:

40-60% for ovarian cancer by age 70 and 3-85% for breast cancer by age 70. A woman’s risks with a BRCA2 alteration are: 16-27% for ovarian cancer by age 70 and 4-86% for breast cancer by age 70.

For women with ovarian cancer who are found to have a BRCA alteration, this now places them at an increased risk to develop breast cancer. For some women, this may be a new risk they were not aware of before the testing, particularly if they have no family history of breast cancer.

For all women with a BRCA2 alteration, there may be a slightly increased risk for colon and pancreatic cancers. Additionally, because the testing process and test results are quite complex (and may have strong emotional consequences) everyone should receive proper genetic counseling before pursuing any BRCA1 and BRCA2 testing. Prenatal BRCA testing is available, but is rarely performed unless accompanied by extensive genetic and psychological counseling.

Treatment and management

As with many other cancers, treatment is determined by the exact size and type of ovarian cancer, so it is often unique to an individual. However, the cornerstone of treatment for ovarian cancer is surgery. This may require a laparotomy procedure in order to remove as much cancerous tissue as possible. Other organs, such as the uterus and fallopian tubes, may also be removed (especially if the cancer has spread there). Chemotherapy, the use of strong chemicals to kill cancer cells, is usually done following surgery. The purpose is to destroy any remaining cancer cells. Radiation therapy (using radioactive waves to kill cancer cells) is not typically used for ovarian cancer because it is not as effective as other treatments.

Screening recommendations for women at high risk to develop ovarian cancer (such as those with a strong family history of the disease) may include:

Pelvic examination every six months or yearly, starting at age 25-35

Transvaginal ultrasound with color Doppler imaging every six months or yearly, beginning at age 25-35

Yearly blood CA-125 testing, starting at age 25-35

For women with a BRCA1 or BRCA2 alteration, they are also at an increased risk for breast cancer. Screening recommendations for them may include:

Examining their own breasts monthly

Examination of their breasts by a physician/nurse every six months or yearly, starting at age 25-35

Mammograms (x rays of the breasts) yearly, starting at age 25-35

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Specific screening programs may vary by physician. In addition to cancer screening, women with BRCA1 or BRCA2 alterations should know about their preventive surgery options. They may consider having their healthy ovaries and/or breasts removed, in order to reduce their risks to develop ovarian and/or breast cancer. Women may be more agreeable to having their ovaries removed because ovarian cancer is difficult to detect. However, this ends their ability to have children and automatically begins menopause for them. Both preventive surgeries greatly reduce a woman’s cancer risk, but they can never eliminate the risk entirely.

For people with cancer or at high risk for it, there often are support and discussion groups available. These may be invaluable for those who feel alone in their situation, because they can meet others who are dealing with the exact same issues.

Prognosis

Because ovarian cancer is not usually diagnosed until it is in an advanced stage, it is the most deadly of all the female cancers of the reproductive organs. As of 2000, only 46% of women diagnosed with ovarian cancer will survive past five years. If ovarian cancer is diagnosed before it has spread to other organs, more than 90% of the patients will survive five years or more. Unfortunately, only 24% of all cancers are found at this early stage.

As of 2001, there appears to be no difference in how a woman with ovarian cancer will do, whether or not she has a BRCA alteration. Because unaffected people in a family with a BRCA alteration may be in high-risk screening programs, the hope is that they may be able to have any of their cancers detected earlier, giving a better prognosis.

Resources

BOOKS

Dollinger, Malin. Everyone’s Guide to Cancer Therapy.

Somerville House Books Limited, 1994. Morra, Marion E. Choices. Avon Books, 1994.

Murphy, Gerald P. Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment and Recovery. American Cancer Society, 1997.

ORGANIZATIONS

American Cancer Society. 1599 Clifton Rd. NE, Atlanta, GA 30329. (800) 227-2345. http://www.cancer.org .

Facing Our Risk of Cancer Empowered (FORCE). 934 North University Drive, PMB #213, Coral Springs, FL 33071. (954) 255-8732. info@facingourrisk.org. http://www

.facingourrisk.org .

Gilda’s Club. 195 West Houston Street, New York, NY 10014. (212) 647-9700. Fax: (212) 647-1151. http://www

.gildasclub.org .

Gynecologic Cancer Foundation. 401 North Michigan Avenue, Chicago, IL 60611. (800) 444-4441.

National Cancer Institute. Office of Communications, 31 Center Dr. MSC 2580, Bldg. 1 Room 10A16, Bethesda, MD 20892-2580. (800) 422-6237. http://www.nci.nih

.gov .

WEBSITES

CancerNet. http://www.cancernet.nci.nih.gov .

National Ovarian Cancer Coalition.

http://www.ovarian.org .

“Ovarian Cancer.” CancerNet. http://www.cancernet.nci.nih

.gov/Cancer_Types/Ovarian_Cancer.shtml .

Deepti Babu, MS

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